1. Technical Field
The present invention relates to an anti-inflammatory pharmaceutical composition comprising a benzopyranyl tetracycle compound.
2. Description of the Related Art
Traditional synthetic organic chemistry has been advanced with the development of target-oriented synthesis. Many organic chemists have conceived and developed various new reactions through the synthesis of diverse natural products. Since the target-oriented synthesis is configured to target and synthesize a specific natural product, the obtained compound may be represented as one of points distributed in chemical space. Thus, target oriented synthesis seems to be very limited in terms of the diversity of compound.
Many efforts have been made to track down more biologically active compounds by improving specific chemical properties of the obtained compound, resulting in the advent of combinatorial chemical synthesis.
Combinatorial chemical synthesis is a new synthetic method for the development of new materials. Whereas conventional organic synthesis methods can require a single reaction for the synthesis of one kind of compound, combinatorial chemical synthesis is efficient enough to synthesize more various and numerous compounds at the same time or to automate the multi-step synthetic process. With combinatorial chemical synthesis, it has become easier to screen biological hit and/or lead compounds of new structures and to optimize the structure and activity thereof. Combinatorial chemical synthesis has been mainly studied in medicinal chemistry, particularly greatly contributing to the study of structure-activity relationship, and also has allowed for various substitution reactions in a specific structure, ensuring skeletal diversity.
Developed as a different and new concept in organic synthesis, diversity-oriented synthesis is configured to synthesize a collection of structurally-diverse compounds distributed in the chemical space and to search for new biologically active compounds among the collection by High Throughput Screening.
In diversity-oriented synthesis, compounds having different core skeletons can be prepared at the same time, and can be constructed into a library from which various different active compounds thus can be identified by various screening methods.
Introduction of the concept of privileged structure to the diversity-oriented synthesis is very advantageous for searching biologically active compounds.
As used herein, the term “privileged structure” refers to a molecular framework found in common in many natural products or biologically active molecules. The application of the privileged structure to diversity-oriented synthesis has been attempted over a long period of time.
Inflammation is a pathological condition of an abscess caused by foreign infectious agents (bacteria, fungi, virus, various kinds of allergens, etc.). For example, when foreign bacteria invade into and proliferate in a tissue, the leukocytes of the body recognize and actively attack the proliferating foreign bacteria, during which leukocytes die and bacteria are killed by the leukocytes. The dead leukocytes and bacterial lysates accumulate in the tissue, forming an abscess. The abscess formed by inflammation can be treated through anti-inflammation activity. Anti-inflammation activity refers to a process that reduces inflammation in which the proliferation of the foreign agent, such as bacteria, is inhibited with the aid of an anti-inflammatory agent, for example, an antibacterial agent, or in which macrophages are activated to digest and excrete the foreign materials accumulated in the abscess. Inflammation refers to a biological protective response of tissues to harmful stimuli. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process for rehabilitating the cells or tissues on which organic lesion has been imposed by the invasion of the stimuli. Factors involved in these serial processes are local vascular tissues, various tissue cells of the body fluid, immune cells, etc. Like the inflammation that is normally induced by foreign pathogens, the defense mechanism for protecting the body is indispensible for survival. However, temporally or spatially inappropriate inflammatory responses play a great role in causing a broad spectrum of diseases including those that are believed to not be related with leukocytes, such as arthritis and Alzheimer disease, as well as those apparently induced by leukocyte components, such as autoimmune diseases, asthma, and atherosclerosis. In such inflammatory diseases, leukocytes are incited to rush to the affected tissue upon an autoimmune response where an antibody inadvertently recognizes a host protein, or by inappropriate triggers, such as accumulated tissue injury, for example, apoptotic bodies of permanent cells, extracellular cholesterol deposits, or intrapulmonary particulates. The leukocytes, although crowded, cannot dispose of all the triggers (for example, leukocytes cannot remove or kill all autoimmune antigen-expressing host cells, or cannot phagocyte too excessively large particles from the host cells). Hence, such diseases occasionally become chronic and continue to release inflammatory cytokines, dispatching additional leukocytes to unnecessary sites where chronic inflammation is thus formed. This inflammatory response is reported to induce chronic progressive diseases such as arteriosclerosis, obesity, insulin resistance, rheumatoid arthritis, glomerulonephritis, cancer, etc. and to play an important role in the progression of senescence.
With regard to the inflammatory response, HMGB has recently been proven to induce inflammation (Korean Patent No. 10-1170032). HMGB (high mobility group box protein) refers to a superfamily of the nuclear proteins that are involved in nucleosome stabilization, gene transcription, and neurite outgrowth. When acetylated or phosphorylated, HMGB proteins are translocated from the nucleus to the cytoplasm and the extracellular space. Also, they are reported to associate with the transmembrane receptors RAGE, TLRs 2 and 4, and syndecan-1 (CD138) to activate NF-κB and ERK1/2.
Leading to the present invention, intensive and thorough research into the treatment of inflammatory diseases resulted in the finding that benzopyranyl tetracycles inhibit the activity of HMGB proteins responsible for inflammation, and thus are useful as anti-inflammatory agents.